Multiple sclerosis (MS) is a complex and heterogeneous inflammatory disorder of the central nervous system characterized by myelin loss, varying degrees of axonal pathology, and progressive neurological dysfunction. The combined effect of many genes, environmental exposures acting during defined periods of life, and their interactions in MS is strongly supported by our own work and others. The involvement of HLA class II genes within the major histocompatibility complex (MHC) on chromosome 6p21 is well-established. The identification of non-MHC determinants of MS susceptibility, while progressing, is far from complete. Similar to other complex diseases, genome-wide association studies (GWAS) have begun to unravel the polygenic etiology of MS. However, variants identified through several large GWAS, to date, explain only a very small proportion of MS heritability. The proposed study describes critical post-GWAS era steps to further our current understanding of MS pathogenesis. First, we will utilize next-generation DNA sequence data, high-throughput genotyping and state-of-the-art bioinformatics methods to fully characterize rare, less frequent and common variants within more than 30 MS genes established through recent GWAS and their contribution to the development of MS and disease expression (Aim 1). Next, we will also comprehensively investigate a number of important life-course exposures including prenatal, perinatal, childhood, adolescent and adult time periods, GxE interactions and risk of MS (Aim 2). Finally, we will study genome-wide DNA methylation profiles in a newly established cohort of clinically isolated syndrome (CIS)/early MS cases and matched controls to identify immune cell specific epigenetic influences on the development of MS (Aim 3). We will utilize extraordinary MS case-control resources nested within the large, population-based membership of Northern California Kaiser Permanente, as well as DNA, genetic and clinical data assembled for this project through the International Multiple Sclerosis Genetics Consortium; more than 10,000 individuals of White/European ancestry will be studied using a suite of statistical methods of analysis. Results from proposed epidemiologic studies of the most important MS genes and causal variants in the context of relevant environmental exposures will inform new functional studies, and have potential to support the development of more effective approaches for prevention, diagnosis and treatment.